Connected Research: The Potential of the PID Graph.

Persistent identifiers (PIDs) provide unique and long-lasting references to entities. They enable unique identification persistently over time and hence play a crucial role in supporting the FAIR (Findable, Accessible, Interoperable, Reusable) principles. In this paper, we describe how the benefits of PIDs can be amplified by connecting them via their metadata. We are introducing the next step in PID infrastructure: the PID Graph. The PID Graph establishes connections between different entities within the research landscape, thereby enabling both researchers and institutions to access new information. The paper closes with three recommendations, which will help to optimize the use and value of PIDs within the research ecosystem.

Recognizing the value of software: a software citation guide.

Software is as integral as a research paper, monograph, or dataset in terms of facilitating the full understanding and dissemination of research. This article provides broadly applicable guidance on software citation for the communities and institutions publishing academic journals and conference proceedings. We expect those communities and institutions to produce versions of this document with software examples and citation styles that are appropriate for their intended audience. This article (and those community-specific versions) are aimed at authors citing software, including software developed by the authors or by others. We also include brief instructions on how software can be made citable, directing readers to more comprehensive guidance published elsewhere. The guidance presented in this article helps to support proper attribution and credit, reproducibility, collaboration and reuse, and encourages building on the work of others to further research.

A data citation roadmap for scholarly data repositories.

This article presents a practical roadmap for scholarly data repositories to implement data citation in accordance with the Joint Declaration of Data Citation Principles, a synopsis and harmonization of the recommendations of major science policy bodies. The roadmap was developed by the Repositories Expert Group, as part of the Data Citation Implementation Pilot (DCIP) project, an initiative of FORCE11.org and the NIH-funded BioCADDIE ( https://biocaddie.org ) project. The roadmap makes 11 specific recommendations, grouped into three phases of implementation: a) required steps needed to support the Joint Declaration of Data Citation Principles, b) recommended steps that facilitate article/data publication workflows, and c) optional steps that further improve data citation support provided by data repositories. We describe the early adoption of these recommendations 18 months after they have first been published, looking specifically at implementations of machine-readable metadata on dataset landing pages.

Everolimus in patients with multiply relapsed or cisplatin refractory germ cell tumors: results of a phase II, single-arm, open-label multicenter trial (RADIT) of the German Testicular Cancer Study Group.

BACKGROUND: Treatment options for patients (pts) with multiply relapsed or refractory metastatic germ cell cancer (GCC) are limited. The mTOR inhibitor everolimus has been approved for the treatment of different solid tumors and was assessed in refractory GCC within this phase II RADIT trial of the German Testicular Cancer Study Group. METHODS: GCC pts progressing during cisplatin-based salvage chemotherapy, or relapsing after high-dose chemotherapy, or failing at least two lines of cisplatin-based chemotherapy were eligible. Prior combination chemotherapy with gemcitabine, oxaliplatin and paclitaxel, or a doublet combination of these drugs was mandatory. Primary endpoint was the progression-free survival rate at 12 weeks. Twenty-five evaluable pts were needed, assuming a 20% two-sided type 1 error and 95% power to reject the null hypothesis of 5% of patients being progression-free after 12 weeks. At least one pt among the first 13 pts being progression-free after 6 weeks was mandatory to complete recruitment. Secondary endpoints were objective response rate, disease control rate (SD + PR + CR), median progression-free survival (PFS), median overall survival (OS), and safety. The trial was registered at http://clinicaltrials.gov as NCT01242631. RESULTS: Twenty-five pts from six German centers were treated with everolimus 10 mg orally once daily until disease progression or unacceptable toxicity between December 2010 and January 2014. 12-week PFS rate was 0%, no objective responses were achieved, and only one pt had stable disease after 6 weeks on treatment as a prerequisite of completing patient accrual accounting for a 6-week disease control rate of 5.4%. Median PFS and OS were estimated at 7.4 weeks and 8.3 weeks, respectively. Toxicity was acceptable, with one treatment discontinuation due to adverse events, and no new safety signals detected. CONCLUSIONS: Targeting the mTOR pathway with single-agent everolimus failed to produce clinically relevant responses in pts with heavily pretreated and/or cisplatin-refractory GCC.

Sharing and reuse of individual participant data from clinical trials: principles and recommendations.

OBJECTIVES: We examined major issues associated with sharing of individual clinical trial data and developed a consensus document on providing access to individual participant data from clinical trials, using a broad interdisciplinary approach. DESIGN AND METHODS: This was a consensus-building process among the members of a multistakeholder task force, involving a wide range of experts (researchers, patient representatives, methodologists, information technology experts, and representatives from funders, infrastructures and standards development organisations). An independent facilitator supported the process using the nominal group technique. The consensus was reached in a series of three workshops held over 1 year, supported by exchange of documents and teleconferences within focused subgroups when needed. This work was set within the Horizon 2020-funded project CORBEL (Coordinated Research Infrastructures Building Enduring Life-science Services) and coordinated by the European Clinical Research Infrastructure Network. Thus, the focus was on non-commercial trials and the perspective mainly European. OUTCOME: We developed principles and practical recommendations on how to share data from clinical trials. RESULTS: The task force reached consensus on 10 principles and 50 recommendations, representing the fundamental requirements of any framework used for the sharing of clinical trials data. The document covers the following main areas: making data sharing a reality (eg, cultural change, academic incentives, funding), consent for data sharing, protection of trial participants (eg, de-identification), data standards, rights, types and management of access (eg, data request and access models), data management and repositories, discoverability, and metadata. CONCLUSIONS: The adoption of the recommendations in this document would help to promote and support data sharing and reuse among researchers, adequately inform trial participants and protect their rights, and provide effective and efficient systems for preparing, storing and accessing data. The recommendations now need to be implemented and tested in practice. Further work needs to be done to integrate these proposals with those from other geographical areas and other academic domains.

Prospective randomized double-blind multicentre phase II study comparing gemcitabine and cisplatin plus sorafenib chemotherapy with gemcitabine and cisplatin plus placebo in locally advanced and/or metastasized urothelial cancer: SUSE (AUO-AB 31/05).

OBJECTIVE: To evaluate the efficacy and safety of gemcitabine and cisplatin in combination with sorafenib, a tyrosine-kinase inhibitor, compared with chemotherapy alone as first-line treatment in advanced urothelial cancer. PATIENTS AND METHODS: The study was a randomized phase II trial. Its primary aim was to show an improvement in progression-free survival (PFS) of 4.5 months by adding sorafenib to conventional chemotherapy. Secondary objectives were objective response rate (ORR), overall survival (OS) and toxicity. The patients included in the trial had histologically confirmed locally advanced and/or metastatic urothelial cancer of the bladder or upper urinary tract. Chemotherapy with gemcitabine (1250 mg/qm on days 1 and 8) and cisplatin (70 mg/qm on day 1) repeated every 21 days, was administered to all patients in a double-blind randomization of additional sorafenib (400 mg twice daily) vs placebo (two tablets twice daily) on days 3-21. Treatment continued until progression or unacceptable toxicity, the maximum number of cycles was limited to eight. The response assessment was repeated after every two cycles. RESULTS: Between October 2006 and October 2010, 98 of 132 planned patients were recruited. Nine patients were ineligible. The final analysis included 40 patients in the sorafenib and 49 patients in the placebo arm. There were no significant differences between the two arms concerning ORR (sorafenib: complete response [CR] 12.5%, partial response [PR] 40%; placebo: CR 12%, PR 35%), median PFS (sorafenib: 6.3 months, placebo: 6.1 months) or OS (sorafenib: 11.3 months, placebo: 10.6 months). Toxicity was moderately higher in the sorafenib arm. Diarrrhoea occurred significantly more often in the sorafenib arm and hand-foot syndrome occurred only in the sorafenib arm. The study was closed prematurely because of slow recruitment. CONCLUSION: Although the addition of sorafenib to standard chemotherapy showed acceptable toxicity, the trial failed to show a 4.5 months improvement in PFS.

What can article-level metrics do for you?

Article-level metrics (ALMs) provide a wide range of metrics about the uptake of an individual journal article by the scientific community after publication. They include citations, usage statistics, discussions in online comments and social media, social bookmarking, and recommendations. In this essay, we describe why article-level metrics are an important extension of traditional citation-based journal metrics and provide a number of example from ALM data collected for PLOS Biology.

Imatinib-induced liver cirrhosis in a patient with advanced gastrointestinal stroma tumor (GIST).

BACKGROUND: The use of imatinib mesylate is associated with a progression free survival of 41 months in first line treatment of metastatic or locally advanced gastrointestinal stromal tumors (GIST) and other studies approved that adjuvant imatinib treatment improves the recurrence-free survival in patients with GIST. Current recommendations include 1 year adjuvant treatment in GIST patients at risk but active studies explore different durations of treatment with an interval of up to 5 years. While the most frequent adverse events (AEs) are blood count alterations, abdominal discomfort and edema, the occurrence of grade 3 or 4 increase of AST or ALT is specified with 2.1% and 2.7% respectively. CASE PRESENTATION: We report a 49-year old male with a gastrointestinal stromal tumor (GIST) of the small bowel who developed liver cirrhosis under adjuvant imatinib treatment. CONCLUSIONS: Our report supports the notion that imatinib-induced hepatotoxicity may lead to acute liver damage with subsequent cirrhotic remodelling. Patients developing grade 3 or 4 hepatotoxicity during imatinib treatment should therefore be carefully evaluated for chronic liver disease.

Progression free survival of first line vascular endothelial growth factor-targeted therapy is an important prognostic parameter in patients with metastatic renal cell carcinoma.

PURPOSE: Intrinsic resistance in metastatic renal cell carcinoma (mRCC) was recently associated with poor overall survival (OS), suggesting that VEGF inhibitor sensitivity may represent a valuable prognostic marker. We explored the duration of progression free survival (PFS) in first-line treatment and other variables as prognostic markers in mRCC. METHODS: Medical records from 119 mRCC patients receiving first line treatment with tyrosine kinase inhibitors (TKI) were retrieved retrospectively. Kaplan-Meier and log-rank analyses were employed on PFS and OS and multivariate Cox proportional hazard model analysed clinical parameters for their prognostic relevance. RESULTS: The median PFS of first line treatment was 8.4 months (95% confidence interval 5.8-11) associated with a median OS of 28.2 months (95% CI 20.9-35.4). Second line therapy with another TKI or mTOR-inhibitor was applied to 81 patients (68%). PFS of any second line therapy was 5.1 and 3.7 months in first line treatment responders and non-responders (p = 0.3), respectively. Univariate analyses revealed bone metastases, prior cytokine treatment, Memorial Sloan Kettering cancer centre (MSKCC) score, objective response rate, Eastern Cooperative Oncology Group (ECOG) performance status, first line PFS with 6 months taken as cut-off parameter and second line treatment as prognostic variables. Multivariate analyses proved first line PFS above 6 months (95% CI 0.154-0.641; HR 0.314), second line treatment (95% CI 0.162-0.657; HR 0.326), MSKCC score (95% CI 1.07-3.392; HR 1.905) and objective response rate (95% CI 0.358-0.989; HR 0.595) to be independent prognostic markers. CONCLUSIONS: The duration of first line PFS is an independent prognostic variable but not predictive for subsequent therapy.

Efficacy of sunitinib re-exposure after failure of an mTOR inhibitor in patients with metastatic RCC.

BACKGROUND: The sequential use of tyrosine kinase inhibitors (TKI) followed by mTOR inhibitors (mTORi) has been recently established for the systemic treatment of metastatic renal cell carcinoma (mRCC). However, subsequent treatment in mTORi-refractory disease remains undetermined. We analyzed the efficacy of sunitinib re-challenge after failure of an mTORi at 2 German centers. PATIENTS AND METHODS: Thirteen patients who failed both sunitinib and an mTORi were analyzed, and all patients were re-exposed to sunitinib. Tumor assessment was performed every 2nd cycle of sunitinib or every 3 months. Tumor response was assessed according to RECIST criteria. RESULTS: Initial treatment with sunitinib was associated with a median progression free survival (PFS) of 21 months. Objective response consisted of 2 (15%) complete remissions and 7 (54%) partial remissions (PR) as best response. At the time of re-exposure, 12 of 13 (92%) patients again showed clinical benefit which was associated with a median PFS of 6.9 months and consisted of 2 (15%) PR and 10 (77%) disease stabilizations. CONCLUSIONS: In sunitinib-responsive patients, re-challenge with sunitinib has been successfully introduced after mTORi-refractory disease, underscoring the at least partially transient nature of TKI resistance in mRCC.

Retrospective analyses of patient characteristics having predictive impact on survival under everolimus.

BACKGROUND: Everolimus is the standard second-line therapy for patients with metastatic renal cell carcinoma (mRCC). We evaluated whether the response to first-line therapy with a tyrosine kinase inhibitor (TKI) has predictive impact on the progression-free survival (PFS) and overall survival (OS) under everolimus. In addition, patient characteristics were evaluated for their predictive impact on the response under everolimus. METHODS: 42 patients with mRCC treated with everolimus (RAD001) within a clinical trial were analyzed. Prior to everolimus, every patient had received at least 1 TKI therapy. Another TKI for second line was given to 15 patients. PFS and OS were estimated according to the Kaplan-Meier method and compared with the log-rank test. RESULTS: Median PFS during everolimus therapy was 5.2 months (range 1.3-17.8). 27 patients (64%) achieved stable disease (SD) or partial remission (PR). Patients with a beneficial PFS under first-line TKI achieved a better OS after start of everolimus treatment (p = 0.05) and so did TKI responders (p = 0.04). A reduced OS was associated with liver metastases (p = 0.04) and high tumor burden (p = 0.01). CONCLUSIONS: A beneficial outcome under prior TKI therapy is predictive for a superior survival in patients treated with everolimus, while high tumor burden and liver metastases impair the OS.

Carboplatin plus weekly docetaxel as salvage chemotherapy in docetaxel-resistant and castration-resistant prostate cancer.

BACKGROUND: There is no proven, effective, standard second-line chemotherapy for castration- and docetaxel-resistant prostate cancer (DRPC). Recent data suggest that carboplatin may be effective in combination with docetaxel in this setting; however, the optimal docetaxel/carboplatin-based regimen is still unclear. AIM OF THE STUDY: We identified 43 consecutive patients with DRPC treated with carboplatin (AUC5 d1) and docetaxel (35 mg/m(2) d1, 8, 15 q4w i.v.) as a second-line or subsequent salvage chemotherapy until discontinuation of therapy due to disease progression or unacceptable toxicity. RESULTS: Decreased prostate-specific antigen (> or =50% PSA) was observed in 22/43 (51.2%, 95% CI, 35.5, 66.7%) patients, with > or =90% reduction in 12/43 patients (27.9%). At the time of analysis, the median follow-up time for all patients was 10.4 months. Median progression-free survival (PFS) for all patients was 6.5 months (95% CI 4.1, 8.9), and median overall survival (OS) was 15.8 months (95% CI 12.1, 18.5). In PSA responders, PFS was 9.5 (95% CI 8.2, 19.0) months versus 3.3 (95% CI 2.6, 4.0) months in PSA non-responders (P < 0.0001; hazard ratio (HR) 0.108) and OS was 24.4 months (95% CI 19.5, 29.4) versus 7.8 (95% CI 5.2, 10.3) months (P = 0.001; HR 0.232). Established prognostic factors were associated with survival. This regimen was reasonably well tolerated, with leukopenia/neutropenia as the most common reversible grade 3/4 toxicity (41.9/39.5%). CONCLUSION: These data suggest that weekly docetaxel plus carboplatin may be an important therapeutic second-line treatment option for patients with DRPC.

Erythropoietin in cancer-related anemia.

PURPOSE OF REVIEW: Erythropoiesis-stimulating agents reduce the transfusion requirements of anemic cancer patients receiving chemotherapy. Risks associated with the use of erythropoiesis-stimulating agents in cancer patients have more recently been identified. RECENT FINDINGS: Several recently published phase III trials and a meta-analysis have shown an increased risk of venous thromboembolism and a decreased survival in anemic cancer patients treated with erythropoiesis-stimulating agents. SUMMARY: To minimize risks associated with erythropoiesis-stimulating agent use in cancer patients, the most recent American Society of Clinical Oncology/American Society of Hematology clinical practice guidelines and Food and Drug Administration recommendations should be followed.

Targeted therapies for patients with germ cell tumors.

BACKGROUND: Patients with advanced germ cell tumors can be cured with cisplatin-based chemotherapy but the outcome remains unsatisfactory for patients with relapsed disease. Targeted therapies have changed the standard of care for many advanced solid tumors. OBJECTIVE: To identify clinically available drugs that have the potential as targeted therapies in germ cell tumors. METHODS: A literature search was carried out for expression and mutation status of receptor tyrosine kinases in germ cell tumors, also a literature and clinical trial database search for completed and ongoing clinical trials with targeted therapies in germ cell tumors. RESULTS/CONCLUSIONS: c-KIT is mutated in some seminomas and bilateral germ cell tumors. Several case reports and small clinical trials with trastuzumab, thalidomide and imatinib were identified and clinical trials with sunitinib and bevacizumab are ongoing. We expect an increased use of targeted therapies in advanced germ cell tumors in the next few years.

European consensus conference on diagnosis and treatment of germ cell cancer: a report of the second meeting of the European Germ Cell Cancer Consensus Group (EGCCCG): part II.

OBJECTIVES: The first consensus report that had been presented by the European Germ Cell Cancer Consensus Group (EGCCCG) in 2004 has found widespread approval by many colleagues throughout the world. In November 2006, the group met a second time under the auspices of the Department of Urology of the Amsterdam Medical Center, The Netherlands. METHODS: Medical oncologists, urologic surgeons, radiation oncologists as well as pathologists from several European countries reviewed and discussed the data that had emerged since the 2002 conference and incorporated the new data into updated and revised guidelines. As for the first meeting the methodology of evidence-based medicine (EBM) was applied. The results of the discussion were compiled by the writing committee. All participants have agreed to this final update. RESULTS: The second part of the consensus paper includes the treatment of metastasised disease, residual tumour resection, salvage therapy, follow-up, and late toxicities. CONCLUSIONS: Whereas the vast majority of the recommendations made in 2004 remain valid 3 yr later, refinements in the treatment of early-stage as well as of advanced-stage testicular cancer have emerged from clinical trials. Despite technical improvements, expert clinical skills will continue to be one of the major determinants for the prognosis of patients with germ cell cancer. In addition, the particular needs of testicular cancer survivors have been acknowledged.

European consensus conference on diagnosis and treatment of germ cell cancer: a report of the second meeting of the European Germ Cell Cancer Consensus group (EGCCCG): part I.

OBJECTIVES: The first consensus report presented by the European Germ Cell Cancer Consensus Group (EGCCCG) in the year 2004 has found widespread approval by many colleagues throughout the world. In November 2006, the group met a second time under the auspices of the Department of Urology of the Amsterdam Medical Center, Amsterdam, The Netherlands. METHODS: Medical oncologists, urological surgeons, radiation oncologists as well as pathologists from several European countries reviewed and discussed the data that had emerged since the 2002 conference, and incorporated the new data into updated and revised guidelines. As for the first meeting, the methodology of evidence-based medicine (EBM) was applied. The results of the discussion were compiled by the writing committee. All participants have agreed to this final update. RESULTS: The first part of the consensus paper describes the clinical presentation of the primary tumor, its treatment, the importance and treatment of testicular intraepithelial neoplasia (TIN), histological classification, staging and prognostic factors, and treatment of stage I seminoma and non-seminoma. CONCLUSIONS: Whereas the vast majority of the recommendations made in 2004 remain valid 3 yr later, refinements in the treatment of early- and advanced-stage testicular cancer have emerged from clinical trials. Despite technical improvements, expert clinical skills will continue to be one of the major determinants for the prognosis of patients with germ cell cancer. In addition, the particular needs of testicular cancer survivors have been acknowledged.

Growth inhibition and apoptosis in human Philadelphia chromosome-positive lymphoblastic leukemia cell lines by treatment with the dual PPARalpha/gamma ligand TZD18.

Treatment of adult Philadelphia chromosome-positive lymphocytic leukemia is rarely successful. We report here the effects of TZD18, a novel dual ligand specific for peroxisome proliferator-activated receptor alpha and gamma (PPARalpha/gamma) on Ph(+) lymphocytic leukemia cell lines BV173, SD1, and SupB-15. Exposure of these cells to TZD18 resulted in growth inhibition in a dose- and time-dependent manner that was associated with G(1) cell cycle arrest. This effect was much stronger than that mediated by the PPARgamma ligand pioglitazone (PGZ), which also belongs to the thiazolidinediones (TZD) class of ligands. However, it may not be mediated through PPARgamma or PPARalpha activation because antagonists of PPARgamma and PPARalpha cannot reverse it. Study of the key regulators of cell cycle progression by Western blot analysis showed that the expression of the cyclin-dependent kinase inhibitor (CDKI) p27(kip1), but not that of p21(cip1), was enhanced, whereas that of c-Myc, cyclin E, cyclin D2, and cyclin-dependent kinases 2 and 4 (CDK-2 and CDK-4) was decreased when these cells were treated with TZD18 (10 or 20 microM). Therefore, the up-regulation of p27(kip1) and the down-regulation of CDK-2 and CDK-4 may, at least in part, account for the G(1) cell cycle arrest. Furthermore, a remarkable induction of apoptosis was observed in the cells treated with this dual ligand. No obvious alteration of bcl-2 protein level occurred, but bax was up-regulated in these TZD18-treated cells. Activation of caspase 8 and caspase 9 by TZD18 was also observed. Importantly, NF-kappaB DNA-binding activity was markedly decreased by the TZD18 treatment. In addition, TZD18 enhanced the growth inhibitory effect of imatinib, a specific tyrosine kinase inhibitor therapeutically used in the treatment of Ph(+) leukemia. Overall, our findings strongly suggest that TZD18 may offer a new therapeutic approach to aid in the treatment of Ph(+) lymphocytic leukemia.